Differential expression of zinc transporter 1 (hZIP1) in normal and malignant prostate tissues from African Americans and European Americans

A28

The genetic and molecular mechanisms responsible for and associated with the development and progression of prostate malignancy are largely unidentified. The peripheral zone is the major region of the human prostate gland where malignancy develops. The normal peripheral zone glandular epithelium has the unique function of accumulating high levels of zinc. In contrast, the ability to accumulate zinc is lost in the malignant cells. This lost ability of the neoplastic epithelial cells to accumulate zinc is a consistent factor in their development of malignancy. Recent studies identified ZIP1 (SLC39A1) as an important zinc transporter involved in zinc accumulation in prostate cells. Furthermore, incidence rates for prostate cancer are higher in African Americans (AAs) than in European Americans (EAs). Our laboratory is attempting to decipher the interaction of environmental and genetic factors that result in the development of prostate cancer in AAs. We hypothesize that since Africa is a mineral-rich continent, and the zinc levels in the water and diet are high, Africans may have genetically downregulated their zinc transporters; otherwise, they would absorb abnormally high levels of zinc, resulting in various serious neurodegenerative and biochemical disorders. It is therefore possible that African descents living in low-zinc areas (i.e. North America, Jamaica, etc) may absorb low zinc when compared with other racial groups because of their inherent downregulation of zinc transporters. Therefore, we investigated the possibility that the down-regulation of hZIP1 gene expression might be involved in the inability of malignant prostate cells to accumulate zinc and have compared the relative zinc uptake and as well gene expressions in 19 pairs of age-matched, Gleason-Score-matched prostate tissues from AAs vs. EAs. Results: 1) generally, hZIP1 gene expression and cellular zinc were prominent in normal peripheral zone glandular epithelium. In contrast, hZIP1 gene expression was markedly down-regulated and zinc was depleted in adenocarcinomatous glands and in prostate intra-epithelial neoplastic foci (PIN). These changes occur early in malignancy and are sustained during its progression in the peripheral zone. 2) As compared to EAs the paired tissues from AAs exhibited a significant down-regulation of hZIP1 and a lower accumulation of zinc (p>001). Conclusion: The studies demonstrate that hZIP1 gene expression is down regulated and zinc is depleted in adenocarcinomatous glands and that AAs as compared to EAs accumulate zinc at much lower levels and this appears to be the due to the down-regulation of hZIP1 transporters. These observations, coupled with the numerous and consistent reports of loss of zinc accumulation in malignant cells in prostate cancer, lead to the plausible proposal that down regulation of hZIP1 is a critical early event in the development of prostate cancer and most likely plays a more significant role in AAs as compared to EAs.